Mother-to-child HIV transmission (MTCT) in the developing world has decreased through the use of antiretrovirals in pregnancy and breastfeeding. Whereas the benchmark of success for programs designed to prevent mother-to-child HIV transmission (PMTCT) has historically focused on vertical HIV-transmission rates, use of antiretrovirals in pregnancy and breastfeeding in resource limited settings has shifted the focus to overall HIV-free infant survival. HIV-exposed uninfected infants (HIV-EUIs) experience higher rates of morbidity and mortality than HIV-unexposed infants in resource limited settings, but the underlying reasons for this disparity are unknown. Identifying the factors that contribute to higher morbidity and mortality among HIV-EUIs and determining methods to improve HIV-free survival is of critical public health importance. The Botswana-Harvard School of Public Health AIDS Institute Partnership (BHP) has been working with the Botswana Ministry of Health to conduct PMTCT and infant survival research for over a decade. Using the research infrastructure of BHP, my specific research aims are: 1) to evaluate the association between infant vitamin D levels at birth and morbidity/mortality in the first 24 months of life, 2) to evalate whether vitamin D levels in HIV-EUIs differ from that of HIV-unexposed infants, 3) to evaluate risk factors for increased morbidity and mortality in HIV-EUIs compared with HIV-unexposed infants, 4) to determine if maternal HAART during breastfeeding is associated with favorable longitudinal growth patterns among HIV-EUIs compared with infant nevirapine prophylaxis during breastfeeding, and 5) to identify potential mediators of favorable growth patterns among HIV-EUIs. My research will be nested within a large NIH-funded clinical trial of HIV-exposed infants in Botswana, and I will also create a comparator cohort of HIV-unexposed infants at these same clinic sites. I will be supported by my co-mentors (Drs. Roger Shapiro and Max Essex), as well as my advisory team (Drs. Shahin Lockman, Michael Hughes, Wafaie Fawzi and Joseph Makhema). These researchers have extensive experience working in the field of MTCT prevention and infant survival. Through my specific research aims and career development plan, I hope to emerge as an independent investigator and achieve my long-term goal of improving the health and survival of HIV-exposed infants in resource limited settings. PUBLIC HEALTH RELEVANCE: There is an increasing number of HIV-exposed but uninfected infants (HIV-EUIs) in Botswana. These infants have higher rates of morbidity and mortality than those who are HIV-unexposed. This study will identify modifiable risk factors associated with increased rates of morbidity and mortality of HIV-EUIs using a large, ongoing NIH-funded cohort as well a new cohort of HIV-unexposed infants. Potentially modifiable risk factors, including maternal and infant Vit D levels, will be an area of focus in order to develop future interventions to improve survival in this vulnerable group.